In a short total synthesis of morphinan compounds, derivatives of 1-benzyl-1,2,3,4-tetrahydroisoquinoline are produced. Certain of these compounds, although highly aromatic and functionalized, can be optically resolved. The optically active enantiomers can serve as important intermediates for both natural and unnatural opioids. As a special function of this invention, certain of the derivatives, namely, 4'-6' and 7'-9', may be hydrogenated to 1'-3' derivatives by asymmetric reduction either of the catalytic or chemical type.
The present application relates to production of chiral intermediates for total synthesis of (-)- and (+)-opioids. Since all medically important opium derivatives, including thebaine, can be manufactured from intermediates prepared in the above-mentioned disclosure, the simple and effective methods described below for synthesis of chiral precursors are of fundamental importance. In addition to affording intermediates for production of (-)-opiods (natural), the present disclosure also permits synthesis of intermediates useful for preparing (+)-opiods which are of importance as antitussive agents and neuropharmacological research tools.
The synthesis outlined for the total short synthesis of dihydrothebainone, dihydrocodeinone, and nordihydrododeinone is shown schematically in the following outline, Flow Diagram 1. ##STR1##
As a general summary of the above chart, the following general description is made commencing with codeine (1).
Racemic dihydrothebainone (19), nordihydrocodeinone (21) and dihydrocodeinone (22) were synthesized in high overall yield from 3-methoxyphenethylamine (4), via the key intermediate (.+-.)-1-bromonordihydrothebainone (18); the route utilized unprotected phenolic intermediates, involved directed Grewe-type cyclization and for 21 and 22, exploited novel oxide bridge closure in the N-nor series.
Heating a mixture of amine (4) and pure acid (5) afforded amide (6). Cyclization of 6 generated an aqueous solution of the 1,2-dehydro derivative of 7, compound 4' shown in Flow Diagram 2. This derivative is the starting point for the novel asymmetric synthesis of this invention. (The possibility for resolution of racemic tetrahydroisoquinoline 7 is suggested in the grandparent application.) Birch reduction with lithium and ammonia afforded 8. Refluxing 8 with PhOCHO or chloral gave 10. A solution of 10 and ethylene glycol generated a solution of ketal 11 and subsequently bromoketal 12 was produced. Grewe-type cyclization produced 17. Refluxing 17 in MeOH-aqueous HCl yielded 18. 19 is available from 18 by hydrogenation in the presence of formaldehyde. Synthesis routes from 18 yield 19, 21, and 22. Specific details are found in the grandparent application (U.S. Pat. No.4,410,700), incorporated by reference. Both the (+)- and (-)-enantiomers of 19, 21, or 22 are available using methodology described in previous applications by K. C. Rice (U.S. Pat. No. 4,410,700, U.S. Ser. No. 476,830 filed Mar. 18, 1983, and U.S. Ser. No. 165,690 filed July 3, 1980).
Conversion of (-)-19, (-)-21 or (-)-22 to (-)-thebaine (3) and (-)-codeine (1) and facile 0-demethylation of the latter to (-)-morphine (2) provide a practical total synthesis of these natural alkaloids. In a similar manner, (+)-19, (+)-21, or (+)-22 afford unnatural (+)-thebaine, (+)-codeine, and (+)-morphine by total synthesis.